normal Defense mechanisms :

1. First line of defense (nonspecific or general) = The mechanical barrier such as skin or
mucous membranes + body secretions (saliva, tears).
2. Second line of defense = The nonspecific processes of phagocytosis and
inflammation.
3. The third line of defense = The immune system (specific).

Definition
 Inflammation is a protective/defensive (nonspecific) body response to tissue injury
that is intended to eliminate the initial cause of cell injury, as well as the necrotic
cells and tissues, and to initiate the process of healing and repair. Inflammation
results in redness, swelling, warmth, and pain (and perhaps loss of function).
 It involves many actors: host cells, blood vessels, proteins and inflammatory cells
and mediators?
Causes of Inflammation
 Trauma
 physical and chemical agents and foreign bodies (such as cuts or
sprains(‫)ا ال لتواءات‬, thermal injury, such as burns, toxicity from certain
environmental chemicals, irradiation, etc).
 Tissue necrosis (from any cause including ischemia or infarction)
 Infections (bacterial, viral, fungal, parasitic)
 Immune reactions (also called hypersensitivity reactions) against environmental
substances (such as allergic reactions) or against “self” tissues.
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General Features of Inflammation
 The components of the inflammatory reaction that destroy and eliminate microbes and dead
tissues are also capable of injuring normal tissues.
Damage occurs if the inflammatory reaction is very strong, prolonged, or inappropriate (e.g.,
autoimmune or allergic reaction).
 Inflammation can be acute (rapid in onset and of short duration) or chronic (insidious of long
duration).
since the inflammatory cells and mediators are short-lived, The Inflammation is normally
controlled and self-limited.
The outcomes of (acute) inflammation is either elimination of the noxious stimulus,
followed by decline of the reaction and repair of the damaged tissue, or persistent injury
resulting in chronic inflammation.
Acute inflammation is an inflammation rapid in onset and of short duration.
The steps of the inflammatory response can be remembered as the five Rs:
(1) Recognition of the injurious agent and vascular Changes
(2) Recruitment of leukocytes
(3) Removal of the agent
(4) Regulation (control) of the response (mainly by the chemical
mediators)
(5) Resolution (repair) 2
Step 1. Recognition of the injurious agent (Microbes, Necrotic Cells, and Foreign Substances) and vascular
changes:

1) A microbe enters a tissue or when the tissue is injured.

2) Resident cells (mainly macrophages , but also dendritic cells, mast cells) sense (detect) the presence of the
infection or damage as well as it will sense the presence of infectious pathogens and substances released
from dead cells by expressing receptors called “pattern recognition receptors” macrophages a large
phagocytic cell found in stationary form in the tissues or as a mobile white blood cell, especially at sites of
infection.

3) Resident cells and plasma protein secrete molecules known as inflammatory mediators (cytokines,
histamine, kinins, serotonin, prostaglandins, and leukotrienes) into the interstitial fluid and blood.

4) These mediators induce(‫ )مؤشر‬vascular changes, affect nerves (pain) and regulate the subsequent
inflammatory response.
The release of chemical mediators’ results in several vascular changes:

(1) Vascular dilation and increased blood flow (hyperemia) (causing erythema and warmth).

(2) Increase in capillary membrane permeability and Extravasation of plasma fluid and proteins (causing
edema):
The resulting protein rich fluid accumulation is called an exudate (results in tissue edema).
The increased fluid dilutes any toxic material at the site, while the globulins serve as antibodies, and
fibrinogen and any blood clot forms a fibrin mesh around the area in an attempt to localize the injurious
agent.
(3) Leukocyte (mainly neutrophil) emigration (recruitment, diapedesis) and accumulation. 3
Step 2. Recruitment of Leukocytes :
The cells and molecules of host defense (including leukocytes and plasma proteins)
normally circulate in the blood, and in inflammation, they have to be stopped and
brought to the offending agent or the site of tissue damage, which are typically
outside the vessels.
 Leukocytes are recruited (attracted) to the area of inflammation by chemotaxis
(in response to a chemotactic chemical such as chemokines released by the
chemoattractant cells).

The sequence of events in the recruitment of leukocytes from the vascular lumen to the
extravascular space (diapedesis) consists of:
(1) Margination and rolling along the vessel wall
(2) Firm adhesion to the endothelium
(3) Transmigration between endothelial cells
(4) Migration in interstitial tissues toward a chemotactic stimulus.

Mechanisms of leukocyte migration through blood vessels (diapedesis). The leukocytes first
roll, then become activated and adhere to endothelium, then transmigrate across the
endothelium, then pierce the basement membrane, and migrate toward chemoattractant
emanating from the source of injury. Different molecules play predominant roles in different
steps of this process: selectins in rolling; chemokines in activating the neutrophils to increase
avidity of integrins; integrins in firm adhesion; and CD31 (PECAM-1) in transmigration.
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Step 3. Leukocytes activation and Removal of the agent:
Once leukocytes have been recruited to the site of infection or tissue necrosis, they must be
activated to perform their functions (by binding to specific receptors) and remove the
offending agent by phagocytosis.
(Note: An unfortunate side effect of the activation of leukocytes may be damage to normal
host tissues).
Leukocyte activation results in:
• Phagocytosis of particles
• Intracellular destruction of phagocytosed microbes and dead cells by substances
produced in phagosomes, including reactive oxygen (ROS) and nitrogen species and
lysosomal enzymes
• Liberation (secretion) of substances that destroy extracellular microbes and dead
tissues, which are largely the same as the substances produced within phagocytic vesicles.
• Production of mediators, including arachidonic acid metabolites and cytokines, that
amplify the inflammatory reaction by recruiting and activating more leukocytes.
Phagocytosis involves
(1) attachment and binding of the particle to receptors on the leukocyte surface.
(2) engulfment of the microbe it will be surrounded by the phydpholipid cell membrane called
phagocytic vacuole.
(3) fusion of the phagocytic vacuole with granules (lysosomes with enzymes) forming the
phagolysosome complex.
(4) killing the microbes or the necrotic tissues by the microbicidal substances (ROS, NO, INOS)
and degradation of ingested microbes by lysosomal enzymes in phagolysosome complex.
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 Chemical mediators
 The Chemical mediators are responsible of the vascular and cellular events in
inflammation.
 Mediators may be produced locally by cells at the site of inflammation, or may
be derived from circulating inactive precursors (typically synthesized by the
liver) that are activated at the site of inflammation.
 AA is a polyunsaturated fatty acid produced
primarily from dietary linoleic acid and
present in the body mainly in its esterified
form as a component of cell membrane
phospholipids (AA metabolites =
eicosanoids).

potent chemotactic
agent for neutrophils

Figure 2–16 Production of arachidonic acid metabolites and their roles in inflammation. Note the enzymatic activities whose inhibition through
pharmacologic intervention blocks major pathways (denoted with a red X). COX-1, COX-2, cyclooxygenases 1 and 2; HETE,
hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid.
Cell-derived mediators
 Cytokines are polypeptide products of many cell types that function as mediators of
inflammation and immune responses.
 Two types:
• Pro- inflammatory cytokines (promote inflammation) such as TNF, IL-1, IL-6
(IL=Interleukin).
• Anti-inflammatory cytokines (counteract or terminate inflammation) such as IL-
10 and TGF-β.
 Chemokines are a class of cytokines that act primarily as chemo-attractants for
different subsets of leukocytes.
Step 4. Regulation (control) of the response (The anti-inflammatory mechanisms)
 Inflammatory reactions subside because:
• many of the mediators are short-lived and are destroyed by degradative
enzymes.
• Several mechanisms that counteract inflammatory mediators function to limit or
terminate the inflammatory response (such as lipoxins, complement regulatory
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proteins, and anti-inflammatory cytokines‫ مثل‬IL-10 and TGF-β)).
Local Manifestations of Acute Inflammation
The cardinal signs (external manifestations) of inflammation are:
• Redness (rubor or erythema) and warmth (heat) caused by (hyperemia)
• Swelling or edema by the shift of protein and fluid into the interstitial space (The resulting
protein rich fluid accumulation is called an exudate).
• Pain results from the increased pressure of fluid on the nerves
• Loss of function may develop if the cells lack nutrients or swelling interferes mechanically with
function. Type of exudates :
Exudate refers to a collection of interstitial fluid formed in the inflamed area. The characteristics
of the exudate vary with the cause of the trauma:
• Serous or watery exudates consist primarily of fluid with small amounts of protein and white
blood cells. Common examples of serous exudates occur with allergic reactions or burns.
• Fibrinous are thick and sticky and have a high cell and fibrin content. This type of exudate
increases the risk of scar tissue in the area.
• Purulent or pus are thick, yellow-green in color, and contain more leukocytes and cell debris as
well as microorganisms. Typically, this type of exudate indicates bacterial infection.
• An abscess is a localized pocket of purulent exudate or pus in a solid tissue ( around a tooth or
in the brain).
• A hemorrhagic exudate may be present if blood vessels have been damaged.

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 Systemic Manifestations of Acute Inflammation

 The systemic effects of inflammation/the acute-phase reaction/the

systemic inflammatory response syndrome.
 The acute-phase response consists of several clinical and pathologic
changes including:
• Fever or pyrexia: a pyrogen is a substance that induces fever (e.g.
Prostaglandin and some cytokines)
• Elevated plasma levels of acute-phase proteins (CRP, SAA, Fibrinogen)
• Leukocytosis
• Rigors (shivering) and Chills (Perception of being cold as the
hypothalamus resets the body temperature)
• Somnolence, Malaise (feeling unwell), Fatigue, Headache and Anorexia
(loss of appetite)
• Septic Shock (in severe bacterial infections) (= dangerously low blood
pressure and abnormalities in cellular metabolism), etc.

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 Diagnostic tests
Diagnostic test:
• Leukocytosis (increased white blood cells in the
blood)
• A differential count (the proportion of each type
of WBC) may be helpful in distinguishing viral
from bacterial infection. Allergic reactions
commonly produce eosinophilia.
• Increased circulating plasma proteins
(fibrinogen, prothrombin, etc.) result from a
response in the liver that increases protein
synthesis.
• Elevated serum C-reactive protein (CRP)

• ESR = Erythrocyte Sedimentation Rate

Note:
Leukocytosis; Differential count ; Elevated (CRP);
Elevated ESR; Increased plasma proteins in the serum
SPECIFIC are nonspecific changes; they do not indicate the
particular cause or site of inflammation.
 Potential Complications of Inflammation
Infection, deep ulcer, Skeletal muscle spasms, Local complications
Examples of Drugs Used to Treat Inflammation

 Acetylsalicylic acid (ASA): Aspirin

 Acetaminophen (such as Tylenol or Paracetamol)
 Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen
 (COX-2 inhibitors) such as Celecoxib (Celebrex): NSAID

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 Treatment of Inflammation – OTHER THERAPIES
Other therapies
• The RICE approach: Rest, Ice, Compression, and Elevation
• Mild-to-moderate exercise
• Physiotherapy and/or occupational therapy
• Rest and adequate nutrition and hydration

 Chronic inflammation is inflammation of prolonged duration (weeks to years).

 In contrast with acute inflammation, chronic inflammation is characterized by a
different set of reactions:
• less swelling and exudate but the presence of more lymphocytes,
macrophages, and fibroblasts (connective tissue cells) than in acute
inflammation.
• Tissue destruction
• More collagen → more fibrous scar tissue forming.
 Chronic inflammation may arise in the following settings:
• Persistent infections by microbes that are difficult to eradicate.
• Immune-mediated inflammatory diseases (hypersensitivity diseases).
• Prolonged exposure to potentially toxic agents. 13
Types of Healing
Healing of a wound area can be accomplished in several ways.
• Resolution (the damaged cells recover): when minimal tissue
damage.
• Regeneration (replacement by identical tissue): when the cells
are capable of mitosis and regeneration.
• Replacement by connective tissue (scar or fibrous tissue
formation): when there is extensive tissue damage, or the cells
are incapable of mitosis.

Complications of healing by scar formation: Loss of Function, Contractures (hernia)

and Obstructions (stenosis) , Adhesions , Hypertrophic Scar Tissue, Ulceration.

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